A cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Authors: MANJUNATHA, UJJINI - Novartis Institutes; VINAYAK, SUMITI - University Of Georgia; ZAMBRISKI, JENNIFER - Washington State University; CHAO, ALEXANDER - Novartis Institutes; SY, TRACY - Washington State University; NOBLE, CHRISTIAN - Novartis Institutes; BONAMY, GHILAIN - Novartis Institutes; KONDREDDI, RAVINDER - Novartis Institutes; ZOU, BIN - Novartis Institutes; GEDECK, PETER - Novartis Institutes; BROOKS, CARRIE - University Of Georgia; HERBERT, GILLIAN - University Of Georgia; SATERIALE, ADAM - University Of Georgia; TANDEL, JAYESH - University Of Georgia; Noh, Susan; LAKSHMINARAYANA, SURESH - Novartis Institutes; LIM, SIAU - Novartis Institutes; GOODMAN, LAURA - Cornell University; BODENREIDER, CHRISTOPHE - Novartis Institutes; FENG, GU - Novartis Institutes; ZHANG, LIJUN - Novartis Institutes; BLASCO, FRANCESCA - Novartis Institutes; WAGNER, JUERGEN - Novartis Institutes; LEONG, JOEL - Novartis Institutes; STRIEPEN, BORIS - University Of Georgia; DIAGANA, THIERRY - Novartis Institutes

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/27/2016
Publication Date: 3/31/2017
Citation: Manjunatha, U.H., Vinayak, S., Zambriski, J., Chao, A.T., Sy, T.L., Noble, C.G., Bonamy, G.M., Kondreddi, R.R., Zou, B., Gedeck, P., Brooks, C.F., Herbert, G.T., Sateriale, A., Tandel, J., Noh, S.M., Lakshminarayana, S.B., Lim, S.H., Goodman, L.B., Bodenreider, C., Feng, G., Zhang, L., Blasco, F., Wagner, J., Leong, J.F., Striepen, B., Diagana, T.T. 2017. A cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis. Nature. https://doi.org/10.1038/nature22337.
DOI: https://doi.org/10.1038/nature22337

Interpretive Summary: Infections that cause diarrhea are responsible for nearly 800,000 deaths every year, mostly among children in the developing world (1). Recently, the apicomplexan parasite Cryptosporidium was found to be one of the leading causes of infectious diarrhea in children (2-5) and is strongly associated with mortality, growth stunting, and cognitive impairment. The major human pathogens causing cryptosporidiosis, C. hominis and C. parvum, infect the epithelial cells of the intestine and, through a mechanism that is not fully understood, trigger severe watery diarrheal symptoms, these are particularly long-lasting and often life-threatening in malnourished and immunocompromised children. Nitazoxanide, the only approved drug for the treatment of cryptosporidiosis has limited efficacy in the most vulnerable patient populations. The recent recognition of cryptosporidiosis as a significant unmet medical need has spawned multiple fledgling efforts to discover new drugs. These efforts seek to leverage recent progress in the molecular genetics of Cryptosporidium to establish high throughput drug screening and the development of animal models suitable for drug discovery. The past decade has seen a revival of phenotypic screening as an approach for infectious diseases drug discovery as it offers both a rapid path toward clinical candidates as well as opportunities to discover and chemically validate novel drug targets. As a member of the phylum Apicomplexa, Cryptosporidium is phylogenetically related to the malaria parasite, Plasmodium. Therefore, we reasoned that critical druggable pathways identified in the malaria parasite would be conserved in Cryptosporidium. Here we describe a selective inhibitor (KDU731) of the C. parvum PI(4)K kinase, showing in vivo efficacy in mouse and neonatal calf cryptosporidiosis models.

Technical Abstract: Diarrheal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of pediatric diarrhea with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor effective treatment. We establish a drug discovery process built on scalable phenotypic assays and mouse models that takes advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity we identified pyrazolopyridines as inhibitors of Cryptosporidium parvum and C. hominis. Oral treatment with the pyrazolopyridine KDU731 results in potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest the Cryptosporidium lipid kinase PI(4)K as a target for pyrazolopyridines and warrant further preclinical evaluation of KDU731 as a drug candidate for the treatment of cryptosporidiosis.